AMP-activated protein kinase (AMPK) represents a new target for the treatment of several diseases, including cancer.
Excess adiposity is associated to different degrees with an increased risk of developing cancers, such as colorectal adenomas, breast cancer (postmenopausal), endometrial cancer, kidney cancer, oesophageal adenocarcinoma, ovarian cancer, prostate cancer, pancreatic cancer, gallbladder cancer, liver cancer and cervical cancer (Calle and Kaaks (2004), Nature Reviews Cancer, 4, 579-591).
Investigations have demonstrated that cancer cells require high rates of fatty acid and protein synthesis for their invasive growth and survival. Studies have shown that inhibition of cancer cell proliferation is possible using AMPK activators. The effects are associated with down-regulation of mTOR and eEF2. AMPK activators also suppress lipid synthesis in tumour cells. It has also been shown that it is a link between AMPK and other anti-cancer targets such as LKB1 and caspase-3 activation.
Cancer cells use glucose at a higher rate compared to normal cells (Warburg O, 1956). Instead of mitochondrial oxidative phosphorylation to produce ATP, cancer cells metabolise glucose via hydrolysis.
Recent studies suggest that hyperinsulinemia is correlated among other things to the incidence of colon and lethal breast and prostate cancer.
Elevated plasma free fatty acids (FFAs) stimulate pancreatic β-cells and is one cause of hyperinsulinemia.
In prostate cancer, hyperinsulinemia has been shown to be prospective risk factor for death and data support that the insulin level could be used as a marker of prostate cancer prognosis (Hammarsten and Högstedt (2005) European Journal of Cancer, 41, 2887).
Several mechanisms may link hyperinsulinemia to the incidence and outcome of breast cancer. Firstly, chronic hyperinsulinemia results in increased production of ovarian testosterone and oestrogen and inhibition of hepatic production of sex hormone binding globulin, a sex-hormonal profile that is associated with breast cancer. Secondly, hyperinsulinemia suppresses hepatic production of insulin-like growth factor binding protein-1 (IGFBP-1), and thus increases circulating levels of IGF-1, which has potent mitogenic effect on breast tissue. Thirdly, insulin itself may have a direct mitogenic effect on breast cancer cells.
The study by Hardy et al ((2005), J. Biol. Chem. 280, 13285) shows that FFAs directly stimulate the growth of breast cancer cells in a GPR40 dependent manner. Moreover, expression studies performed on tumor tissue isolated from 120 breast cancer patient shows a frequent expression of GPR40 emphasizing the clinical relevance of the findings of Hardy (see, for example, Ma et al, Cancer Cell (2004) 6, 445).
Another expression study on clinical material from colon cancer patients suggests that similar mechanisms could be relevant also in these malignancies (see http://www.ncbi.nlm.nih.gov/projects/geo/gds/gds_browse.cgi?gds=263).
Cancer cells in general exhibit an aberrant metabolism compared to non-transformed cells. Neoplastic cells synthesise lipids to a much larger extent than their normal counterparts and metabolise glucose differently. It has been suggested that this aberrant metabolism constitutes a therapeutic target. By interfering with one or, preferably, several of the pathways controlling cellular metabolism, cancer cells would be more sensitive than non-transformed cells, thus creating a therapeutic window. Examples of pathways/targets include glycolysis interfering agents, lipid synthesis pathway, AMPK activating agents and agents affecting mitochondrial function.
AMP-activated protein kinase (AMPK) is a protein kinase enzyme that consists of three protein sub-units and is activated by hormones, cytokines, exercise, and stresses that diminish cellular energy state (e.g. glucose deprivation). Activation of AMPK increases processes that generate adenosine 5′-triphosphate (ATP) (e.g., fatty-acid oxidation) and restrains others such as fatty acid-, glycerolipid- and protein-synthesis that consume ATP, but are not acutely necessary for survival. Conversely, when cells are presented with a sustained excess of glucose, AMPK activity diminishes and fatty acid-, glycerolipid- and protein-synthesis are enhanced. AMPK thus is a protein kinase enzyme that plays an important role in cellular energy homeostasis. Therefore, the activation of AMPK is coupled to glucose lowering effects and triggers several other biological effects, including the inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, and the reduction of hyperinsulinemia.
Given the above, AMPK is a preferred target for the treatment of the metabolic syndrome and especially type 2 diabetes. AMPK is also involved in a number of pathways that are important for many different diseases (e.g. AMPK is also involved in a number of pathways that are important in CNS disorders, fibrosis, osteoporosis, heart failure and sexual dysfunction).
AMPK is also involved in a number of pathways that are important in cancer. Several tumour suppressors are part of the AMP pathway. AMPK acts as a negative regulator of the mammalian TOR (mTOR) and EF2 pathway, which are key regulators of cell growth and proliferation. The deregulation may therefore be linked to diseases such as cancer (as well as diabetes). AMPK activators may therefore be of utility as anti-cancer drugs.
Current anti-diabetic drugs (e.g. metformin, glitazones) are known to not be significantly potent AMPK activators, but only activate AMPK indirectly and with low efficacy. However, due to the biological effects of AMPK activation at the cell level, compounds that are AMPK activators, and preferably direct activators of AMPK, may find utility as anti-cancer drugs, as well as for the treatment of many other diseases.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains.
Keilen et al., Acta Chem. Scand. 1988, B42, 362-366 describe the formation of 1,2,4-thiadiazolo activated pyrimidinones. There is also disclosed a specific 1,2,4-thiadiazolo-3-ones. However, the document does not disclose any biological effects associated with the disclosed compounds, nor does it disclose 1,2,4-thiadiazolo-3-ones substituted at the 5-position with an amide or amine derivative bearing at least one substituted aromatic ring.
Kaugars et al., J. Org. Chem. 1979, 44(22), 3840-3843 describe 5-phenyl- and 5-methyl-substituted phenyl urea derivatives of 1,2,4, thiadiazol-3-one that are substituted in the 2-position with a methyl group. There is no mention of any biological effects associated with the disclosed compounds.
Cho et al J. Heterocyclic Chem. 1991, 28, 1645-1649 discloses various 1,2,4-thiadiazol-3-ones. However, there is no disclosure of such 1,2,4-thiadiazol-3-ones, in which the 2-position and 5-position contain substituents bearing an aromatic ring.
U.S. Pat. No. 4,093,624 describes 1,2,4 thiadiazolidin-3-one compounds, described as having antimicrobial activity, which are substituted by a —NH2 or —NHAc in the 5-position and H or ribofuranosyls in the 2-position. There is no disclosure of 1,2,4-thiadiazol-3-ones in which the 2-position and 5-position contain substituents bearing an aromatic ring.
Castro et al., Bioorg. Med. Chem. 2008, 16, 495-510 describes thiadiazolidinone derivates as GSK-3β □inhibitors that are potentially useful for the treatment of Alzheimer's disease. There is no mention that such compounds may be useful as AMPK activators. Further, there is no mention of 1,2,4-thiadiazol-3-ones substituted at the 5-position with an amide or amine derivative bearing at least one substituted aromatic ring.
Martinez et al. Bioorg. Med. Chem. 1997, 7, 1275-1283 describes arylimino-1,2,4-thiadiazolidinone derivatives as potassium channel openers that are potentially useful for the treatment of diseases involving smooth muscle contraction (e.g. hypertension). However, there is no disclosure of such thiadiazolidinones substituted at the 2-position with an aromatic group.
US patent application publication number 2003/0195238 describes thiadiazolidine derivates as GSK-3β □inhibitors that are potentially useful for the treatment of Alzheimer's disease. However, this document mainly relates to thiadiazolidines substituted by two carbonyl/thiocarbonyl groups (thereby forming e.g. a 3,5-dioxo-thiadiazolidine or a 3-thioxo-5-oxo-thiadiazolidine). Further, it mainly relates to compounds in which both nitrogen atoms of the thiadiazolidine are substituted. The document does not relate to thiadiazolidines substituted at the 2-position with a group bearing an aromatic group and at the 5-position with an amino or amido derivative bearing an aromatic group.
International patent applications WO 2007/010273 and WO 2007/010281 both disclose e.g. thiazolidin-4-one and 1,1-dioxo-1,5-dihydro-[1,4,2]dithiazole compounds that are able to antagonize the stimulatory effect of FFAs on cell proliferation when tested in an assay using a human breast cancer cell line (MDA-MB-231). Such compounds are thus indicated in the treatment of cancer and/or as modulators of FFAs. However, these documents do not disclose or suggest thiadiazolidinones.